Background <p>The abscopal effect, tumor regression at distant, non-irradiated sites following localized radiotherapy, is rarely observed, even in immunogenic cancers such as renal cell carcinoma. Current strategies have largely failed to reliably enhance this phenomenon. This study aimed to develop and evaluate a novel therapeutic approach to potentiate the abscopal effect using a combination of tumor-targeted liposomal everolimus and YM155 (EY-L), radiation, and interleukin-2 (IL-2).</p> Methods <p>A trimodal therapy comprising EY-L, localized radiation, and systemic IL-2 was tested in two murine renal cancer models (Renca and LVRCC67) using a bilateral tumor setup to distinguish local and distant tumor responses. The efficacy of the triple therapy was compared to that of single and dual combinations. Downstream analyses including immunohistochemistry, CD8⁺ T cell depletion, and spatial transcriptomics were performed to investigate potential mechanisms underlying the observed effects.</p> Results <p>In the Renca model, the EY-L + R + IL-2 triple combination significantly suppressed growth in both irradiated and non-irradiated tumors, demonstrating a robust enhancement of the abscopal effect. Dual combinations failed to elicit similar systemic responses, underscoring the necessity of the full triple regimen. Mechanistic analyses revealed increased infiltration of CD8⁺ T cells and reduced CD163⁺ macrophages in non-irradiated tumors, suggesting that enhanced systemic anti-tumor immunity mediates the effect. The LVRCC67 model showed similar trends, however the effects were modest, likely attributable to difference in immune responsiveness.</p> Conclusion <p>This study presents a novel and effective strategy to induce the abscopal effect through a synergistic combination of targeted drug delivery, radiotherapy, and immunotherapy. The approach offers strong translational potential for improving radioimmunotherapy outcomes in renal and potentially other immunogenic cancers.</p>